Clinical gene therapy for cardiovascular disease remains achievable. To date, however, preclinical studies and clinical trials have highlighted shortfalls in viral gene delivery to vascular cells. These include poor efficiency, poor target tissue selectivity, the presence of pre-existing neutralizing antibodies and immunogenicity generated by the host to vectors such as adenovirus. These important issues require careful consideration when applying viral vectors for gene therapy. Each delivery vector requires precise optimization and tailoring for each disease application since parameters relating to vector : tissue exposure time, route of delivery and target cell type vary considerably. Optimization can be achieved through modification of the structure of the virus capsid proteins and expression cassette to generate vectors that are highly selective and efficient for target cell binding and entry as well as instilling transcriptional control and/or longevity on transgene expression. This ultimately will improve the efficacy and toxicity profiles of gene delivery vectors and has become a very important area in gene therapy. Here, we review recent advances in the targeting of viral gene delivery vectors to the vasculature.